The present invention relates to novel forms of sustained-release (SR) microgranules containing Diltiazem as active principle.
Diltiazem is a calcium-antagonist benzothiazepine derivative which is useful for the treatment of arterial hypertension. It may be administered in various forms: tablets, injectable solutions or gelatin capsules containing sustained-release granules. The latter have the advantage of allowing the administration to be taken as a single dose required for daily treatment.
Various forms of Diltiazem SR microgranules have been described in the prior art, the most advantageous being that described in patent application EP-A-0,149,920, comprising a core combining Diltiazem with a water-soluble organic acid, in particular fumaric acid. The reason for this is that Diltiazem, or its pharmaceutically acceptable salts, are sparingly soluble at neutral or basic pH, and the presence of a water-soluble organic acid has proven to be particularly important, making it possible to create a buffered acidic microenvironment, promoting both the dilution and the absorption of the Diltiazem in areas of the digestive tract where the pH is too high. It has, nevertheless, been observed that for these SR forms, the solubilization and absorption of Diltiazem were dependent on the absorption of food, and are different when uptake of the microgranules is carried out on an empty stomach or during meals.
Organic-acid-free SR microgranules have been described in patent application EP-A-0,613,370. The core of the microgranules consists here of a neutral grain coated with a succession of layers of a water-soluble polymer, on the one hand, and of Diltiazem on the other hand.
For these various forms, the sustained release of the active principle is ensured by one or more layers coating the core of the microgranules, generally combining two types of film-forming polymer material, one being water-insoluble and the other water-soluble.
The present invention relates to a novel form of SR microgranules containing Diltiazem, or a pharmaceutically acceptable salt thereof, which is free of water-soluble organic acid, making it possible to obtain solubilization and absorption of the active principle which are at least equivalent to those obtained in the presence of an acid. In addition, the present invention relates to a simple novel form of SR microgranules containing Diltiazem, which is easy to prepare.
The microgranules according to the invention comprise a neutral granular support coated with an active layer comprising Diltiazem or a pharmaceutically acceptable salt thereof, a surfactant and a binder, and a layer which ensures sustained release of the active principle (referred to hereinbelow as the SR layer).
More particularly, the microgranules in accordance with the present invention may be of several categories.
The first category is represented by microgranules whose SR layer ensures slow sustained release of the active principle.
The second category is represented by microgranules whose SR layer ensures rapid sustained release of the active principle.
The difference between these two categories of monolayer microgranules lies essentially in the thickness of the coating agent contained in the SR layer. Indeed, the thicker this SR layer is, the slower will be the diffusion of the active principle.
The dissolution profile of each of these two types of microgranule is determined in vitro using water as dissolution medium, and gives the following specifications:
The present invention also relates to a third category of microgranules resulting from the coating of the SR layer which ensures slow sustained release of the active principle, that is to say of the SR layer of microgranules of the first category above, from another active layer comprising:
Diltiazem or a pharmaceutically acceptable salt thereof as active principle,
a surfactant, and
a binder,
itself coated with an external layer which ensures rapid sustained release of the active principle contained in this active layer.
In other words, these so-called xe2x80x9cbilayerxe2x80x9d microgranules consist, from the centre to the periphery, of a neutral granular support, of a first active layer, of an SR layer ensuring slow sustained release of the active principle contained in the first active layer, of a second active layer and of an SR layer ensuring rapid sustained release of the active principle contained in the second active layer.
It is understood that for the so-called xe2x80x9cbilayerxe2x80x9d microgranules, only the specifications described above and corresponding to the slow and mixed microgranules can be applied.
Advantageously, a so-called protective coating or intercalating layer is applied to the microgranule between the SR layer ensuring slow sustained release of the active principle and the second layer of active principle.
Indeed, it has been shown that during application of the second layer of Diltiazem, and/or during dissolution of the microgranules, interactions are established between the Diltiazem and the SR layer located between the two active layers, thereby leading to the modification of sustained release of the Diltiazem contained in the first active layer. This intercalating layer acts as it were as insulation between the two layers concerned, protecting them from each other. Another means of obtaining the same result would consist in using for the SR layer in question a coating agent which does not interact with the Diltiazem.
The neutral granular support consists of any pharmaceutically acceptable neutral granular support, with an average diameter of between 0.4 and 0.9 mm, preferably 0.4 and 0.6 mm. These are preferably grains consisting of sucrose and starch in a weight ratio in the region of 75/25, such as those described under the name xe2x80x9cSugar Spheresxe2x80x9d (Handbook of Pharmaceutical Excipients, 2nd Ed., The Pharmaceutical Press, London, 1994).
The hydrochloride is preferably among the pharmaceutically acceptable salts of Diltiazem.
The surfactant may be an anionic, nonionic, cationic or amphoteric surfactant. It is preferably an anionic surfactant. Among the anionic surfactants are alkali metal (C10-C20)alkyl sulphates, preferably sodium lauryl sulphate, alkali metal (C10-C20)alkyl sulphonates or alkali metal (C10-C20)alkyl benzenesulphonates. The term alkali metal is preferably understood to refer to sodium or potassium.
The binder consists of any pharmaceutically acceptable binder which is useful for coating neutral granular supports, in particular pharmaceutically acceptable polymers such as the polyvinylpyrrolidones described under the name povidone (Handbook of Pharmaceutical Excipients, 2nd Ed., The Pharmaceutical Press, London, 1994), or hydroxypropyl methyl celluloses (HPMC), polyethylene glycols (PEG), etc.
The active layer comprising the Diltiazem may also comprise other common additives, such as a plasticizer.
In general, the active principle/neutral granular support weight ratio is in the region of 4/1. The term active principle is understood to refer to Diltiazem or the pharmaceutically acceptable salts thereof.
The active principle/surfactant weight ratio is advantageously between 99/1 and 95/5, preferably about 98/2.
The active principle/binder weight ratio is itself between 99/1 and 90/10, preferably in the region of 97/3.
The monolayer microgranules according to the invention preferably comprise the following components for the support and the active layer, the percentages being given on a weight basis for a total of 100:
The bilayer microgranules according to the invention preferably comprise the following components for the support and the active layers, the percentages being given on a weight basis for a total of 100:
Each SR layer consists of a coating agent which ensures the sustained release, optionally combined with one or more common additives, in particular a bioavailability adjuvant and/or a plasticizer and/or a lubricant.
The coating agent ensuring the sustained release is preferably a water-insoluble film-forming polymer, such as polymethacrylates (Handbook of Pharmaceutical Excipients, 2nd Ed., The Pharmaceutical Press, London 1994), in particular poly(ethyl acrylate, methyl methacrylate, trimethylammoniumethyl methacrylate chloride), which are marketed under the brand name Eudragit(copyright) RS.
The bioavailability adjuvant is preferably a fatty acid ester of polyoxyethylene, in particular those described under the name Polysorbate (Handbook of Pharmaceutical Excipients, 2nd Ed., The Pharmaceutical Press, London, 1994), in particular those marketed under the brand name Montanox(copyright).
The lubricant consists of a pharmaceutically acceptable common lubricant used in the preparation of microgranules, in particular talc.
The plasticizer is a pharmaceutically acceptable common plasticizer used for the preparation of microgranules, in particular esters of citric, phthalic and sebacic acids, in particular aliphatic esters such as triethyl citrate, dibutyl sebacate or diethyl phthalate, and mixtures thereof.
Preferably, a phthalic acid ester is used for each active layer and a mixture of esters of citric and sebacic acids is used for each SR layer.
When it is present, the protective coating or intercalating layer consists of a methacrylic type polymer, a plasticizer, a lubricant and optionally a bioavailability adjuvant.
The monolayer microgranules according to the invention advantageously have the following final composition, the percentages being expressed on a weight basis for a total of 100%:
The bilayer microgranules according to the invention advantageously have the following final composition, the percentages being expressed on a dry weight basis for a total of 100%:
The active principle content of each active layer may be identical or different depending on the rate and the amount of active principle which it is desired to release over time. The necessary adaptations depending on the aim to be achieved are within the capability of any person skilled in the art.
The microgranules according to the invention are prepared according to the usual techniques for mounting the active principle onto the neutral granular support followed by coating with the SR layer, the operation being repeated for the bilayer microgranules.
The active principle is mounted by discontinuous spraying of an aqueous-alcoholic solution containing the binder, the surfactant and optionally the plasticizer, in alternance with sequences of dusting of the active principle and sequences of leaving to stand.
The Diltiazem microgranules thus obtained are then screened and dried.
Coating with each SR layer is then carried out by spraying an aqueous suspension containing the coating agent and the usual additives. The SR microgranules thus obtained are then screened and dried.
This operation of coating with each SR layer is repeated as many times as required to obtain the desired release kinetics.
Other characteristics of the microgranules according to the invention will become apparent on reading the examples which follow in which rotating turbomixers are preferably used, it also being possible to use any other coating machine, in particular one with a fluidized bed of the Glatt or Niro type, with the usual modifications known to those skilled in the art.
1.1 Preparation of the Mounting Solution
The mounting excipients are weighed out in the following proportions:
The 95% ethyl alcohol is poured into a first stainless steel mixer and the PVP K 17 is then introduced portionwise with stirring. Stirring is continued until the solution is homogeneous. An alcoholic 15% PVP K 17 solution is obtained.
The purified water is poured into a second stainless steel mixer and the sodium lauryl sulphate is then introduced portionwise with stirring. Stirring is continued until the solution is homogeneous. An aqueous 7.5% sodium lauryl sulphate solution is obtained.
The above two solutions are then mixed together and the diethyl phthalate is added with stirring.
1.2 Mounting of the Diltiazem
The support grains (sugar spheres) are placed in a rotating coating turbomixer. The active principle (hydrochloride) is mounted on the support grains by discontinuous spraying of the mounting suspension obtained above, in alternance with sequences of dusting of the active principle and sequences of leaving to stand. The dusting operation is repeated until the desired active principle content is obtained. The microgranules obtained are screened and are then dried.
Immediate-release microgranules of the following composition are obtained, the percentages being given on a weight basis:
for a Diltiazem (hydrochloride) content of 735.75 mg/g of microgranules.
1.3 Preparation of the Coating Solution
The following coating excipients are weighed out in the proportions indicated:
The purified water is poured into a stainless steel beaker and the Montanox 80 DF, the triethyl citrate and then the dibutyl sebacate are introduced portionwise with stirring. Stirring is continued until the solution is homogeneous, and the talc is then introduced portion-wise with stirring. Lastly, the Eudragit RS 30 D is added with stirring being continued until the suspension is homogeneous and then throughout the coating phase.
1.4 Coating of Microgranules
The microgranules obtained above are placed in a rotating coating turbomixer and they are then coated by continuous spraying of the solution obtained above. The mass of coated microgranules obtained is screened and they are then dried in a rotating turbomixer at room temperature, or by blowing with cold air if the room temperature is above 24xc2x0 C.
This operational sequence is repeated as many times as required to obtain the desired kinetics.
Lastly, the SR microgranules obtained are lubricated by adding talc during the mixing phase.
By carrying out the process described in Example 1, varying the amount of Eudragit RS 30 D and of excipients, microgranules with the compositions described in Table I below are obtained.
Microgranules 4 consist of a mixture of microgranules 2 and 3, lubricated with 0.5% talc (%=weight of talc/weight of microgranules to be lubricated).
Microgranules 5 are obtained by a second coating of 400 g of microgranules 2 with the suspension of Example 1.1.
Microgranules 6 are obtained by a second coating of 500 g of microgranules 2 with the suspension of Example 1.1.
Microgranules 7 consist of a mixture of microgranules 5 and 6, lubricated with 0.5% talc.
Microgranules 8 are obtained by a second coating of 400 g of microgranules 2 with the suspension of Example 1.1.
Microgranules 9 consist of a mixture of microgranules 5 and 8, lubricated with 0.5% talc.
The above microgranules are subjected to a study of the kinetics of dissolution in water over 24 hours. The results obtained are summarized in Table II below, expressed as a percentage of active principle in solution relative to the total active principle.
The bioequivalence of gelatin capsules dosed with 300 mg of Diltiazem and containing the microgranules of composition 9 (Diltiazem CD) was compared in vivo with Cardizem(copyright) CD 300 mg marketed by the company Marion Merrell Dow Inc. in the United States.
The studies were carried out on three groups of 12 patients, by measuring the concentration of active principle in the plasma.
For the first group, the Cardizem(copyright) CD was administered on an empty stomach (reference).
For the second group, the Diltiazem CD was administered on an empty stomach (xe2x80x9ctest-fastxe2x80x9d).
For the third group, the Diltiazem CD was administered with simultaneous administration of a standardized meal, the American xe2x80x9cbreakfastxe2x80x9d (xe2x80x9ctest-fedxe2x80x9d).